SWI/SNF chromatin remodelling complex contributes to clearance of cytoplasmic protein aggregates and regulates unfolded protein response in Saccharomyces cerevisiae

Abstract

Chromatin remodelling complexes are multi-subunit assemblies, each containing a catalytic ATPase and translocase that is capable of mobilizing nucleosomes to alter the chromatin structure. SWI/SNF remodelling complexes with higher DNA translocation efficiency evict histones or slide the nucleosomes away from each other making DNA accessible for transcription and repair machinery. Chromatin remodelling at the promoter of stress-responsive genes by SWI/SNF becomes necessary during the heat and proteotoxic stress. While the involvement of SWI/SNF in transcription of stress-responsive genes has been studied extensively, the regulation of proteostasis by SWI/SNF is not well understood. This study demonstrates critical functions of SWI/SNF in response to cadmium-induced proteotoxic stress. Deletion of either ATPasetranslocase subunit of SWI/SNF complex (Swi2/Snf2) or a regulatory subunit Swi3 abrogates the clearance of cadmium-induced protein aggregates. Our results suggest that Snf2 and Swi3 regulate the protein folding in endoplasmic reticulum (ER) that reduces the chances of forming unfolded protein aggregates under the proteotoxic stress of cadmium. The Ire1-mediated unfolded protein response (UPR) maintains ER homeostasis by upregulating the expression of chaperones and ER-associated degradation (ERAD) components. We found that Snf2 maintains normal oxidative environment essential for Ire1 activity. Deletion of SNF2 reduced the Ire1 activity and UPR, indicating involvement of Snf2 in Ire1-mediated ER proteostasis. Together, these findings suggest that SWI/SNF complex regulates ER homeostasis and protein folding crucial for tolerating proteotoxic stress.

The Role of BRG1 in Antioxidant and Redox Signaling

“…In the presence of ER stress, the UPR uses evolutionarily conserved signaling pathways to restore normal cell function and inhibit apoptosis, which are necessary and sufficient to alleviate protein aggregation and ER stress [ 81 ]. BRG1 maintains the basal level of inositol-requiring enzyme 1 (Ire1) activity by reducing oxidative stress in the ER network, which promotes UPR regulation and the clearance of cytoplasmic protein aggregates to maintain ER homeostasis [ 82 ]. These data indicate that BRG1 plays a critical role in oxidative stress by maintaining ER homeostasis ( Figure 1 ).…”

The ATP-dependent SWI/SNF and RSC chromatin remodelers cooperatively induce unfolded protein response genes during endoplasmic reticulum stress

“…The tunicamycin and cadmium have a different mode of toxicity. While tunicamycin blocks the initial step of N-linked protein glycosylation, cadmium targets the nascent peptides in the ER lumen for aggregation, probably by binding to their exposed thiol groups (2,97). Therefore, possibly, the cells accumulate a higher number of nascent peptide aggregation in cadmium than tunicamycin, demanding the activation of disaggregating chaperones and degradation machinery.…”

The Effect of Calorie Restriction on Protein Quality Control in Yeast

“…In terms of ER stress, CR leads to an increase in unfolded proteins in the ER, which in turn leads to the activation of the UPR and consequently autophagy in an Atg1-dependent manner [36,[40][41][42]56]. A disruption of the UPR also increases the number of misfolded proteins in the ER in response to proteotoxic stress [56,57]. The chromatin remodelling complex SWI/SNF has been suggested to be necessary for ER stress signalling upon heat and proteotoxic stress [57].…”

“…A disruption of the UPR also increases the number of misfolded proteins in the ER in response to proteotoxic stress [56,57]. The chromatin remodelling complex SWI/SNF has been suggested to be necessary for ER stress signalling upon heat and proteotoxic stress [57]. For example, deletions within this complex have been shown to increase misfolded protein accumulation in the ER in response to cadmium [57,58].…”

“…The chromatin remodelling complex SWI/SNF has been suggested to be necessary for ER stress signalling upon heat and proteotoxic stress [57]. For example, deletions within this complex have been shown to increase misfolded protein accumulation in the ER in response to cadmium [57,58]. Misfolded proteins can also be degraded through ER-associated degradation (ERAD), whose functionality is necessary for a normal lifespan [56].…”